The following discussion of the background of the invention is merely provided to aid the reader in understanding the disclosure and is not admitted to describe or constitute prior art.
Ischemic organ injury, and the related condition of ischemia/reperfusion injury, is accompanied by changes in signaling molecules and metabolic effectors that can, independently or in concert, trigger cell death in its various forms. These include changes in intracellular pH, calcium, ceramide, free radicals, hypoxia and adenosine triphosphate (ATP) depletion. While all of these factors may be significantly altered as a consequence of acute necrotic cell death, they can also be specific effectors of apoptotic death under certain circumstances.
The contributions of apoptotic cell death and cellular necrosis to functional deterioration of the organ in ischemic conditions such as myocardial infarction and stroke are well established. Myocardial infarctions generally result in an immediate depression in ventricular function due to myocardial cell necrosis and apoptosis. These infarctions are also likely to expand, provoking a cascading sequence of myocellular and structural events which ultimately result in adverse cardiac remodeling. In many cases, this progressive myocardial infarct expansion and adverse ventricular remodeling (thinning of left ventricular wall, scar tissue formation) leads to deterioration in ventricular function and heart failure.
Ischemic renal injury has been traditionally associated with tubular cell necrosis along with obstructive cast formation, disruption of architecture, and a significant inflammatory response. More recently apoptosis has emerged as a significant mode of cell death during ischemic renal injury. While the contribution of apoptotic cell death to functional deterioration of the organ is obvious in conditions like myocardial infarction and stroke, it is less clear how apoptotic dropout of tubular cells can impact glomerular filtration rate (GFR). Nevertheless, recent reports have demonstrated that interference with the apoptotic program does translate into a protective effect on renal function.
Despite considerable advances in the diagnosis and treatment of conditions related to apoptosis and cellular necrosis, there remains a need in the art for prophylactic and therapeutic approaches for the treatment of these conditions.